Clinical & Experimental Cardiology
Open Access
ISSN: 2155-9880
ISSN: 2155-9880
Guy Salama
University of Pittsburgh School of Medicine, USA
Scientific Tracks Abstracts: J Clin Exp Cardiolog
Relaxin, a hormone first described in pregnancy, has more recently been shown to have important cardiovascular effects. Relaxin activates a wide range of signaling pathways through its receptors, RXFP1/2 which are expressed in most organs. RXFP1 signaling stimulates cAMP, NO and several growth factors and inhibits angiotensin-II and TGF-�?² effects. RLX increases systemic arterial compliance and reverses fibrosis in multiple organs. In the RELAX-AHF trials, patients with acute decompensated heart failure (HF) received RLX (i.v. 2-days) resulting in reduced mortality (37%, 6-months-later) compared to standard of care. Our studies showed that RLX suppresses atrial fibrillation in spontaneously hypertensive and in aged rats through a marked increase in conduction velocity (CV). CV elevation was associated with the remodeling of the extracellular matrix (â�?�?fibrosis: â�?�?collagen I&III, â�?�?TGF�?²-1, â�?�?SMA-�?±, â�?�?MMP-6&9) and of electrical properties (â�?�?Connexin43 (Cx43) phosphorylation, â�?�?INa, â�?�?Nav1.5). Here, we show for the first time a close interplay between RLX and Wnt signaling. Male aged rats (24-months) were treated with RLX (400�?¼g/kd/day, 2-weeks) or a vehicle delivered with implantable mini-pumps. Langendorff hearts were optically mapped, then analyzed by immunofluorescence, voltage-clamp and RT-PCR. RLX-treatment increased Wnt1 (80%) and �?²-catenin (72%) at intercalated disks (ID) and reversed the lateralization of Cx43 (without changing Cx43 levels) increasing and their co-localization with �?²-catenin at ID. RLX also reduced Wnt3a (83%) and increased Nav1.5 (80%) and INa (46%) (p<0.02, n â�?¥ 4 hearts/group). These robust genomic effects of RLX may explain its long-lasting protective actions in HF patients who were treated with RLX (iv) for merely 2-days.
Guy Salama has completed his PhD in Biophysics and Biochemistry and a Post-doctroal fellowship at the University of Pennsylvania. He is a pioneer in the development of optical probes of membrane potential, high spatial and temporal-resolution imaging of electrical activity and Ca2+ transients and the elucidation of arrhyhtmia mechanisms. He has made significant contributions to elucidate the mechanisms underlying sex differences in long QT-related arrhyhtmias and demonstrated the genomic modulation of cardiac ion channels by estrogen. He has published more than 125 papers in top-tiered journals and has served on numerous study sections for the NIH and the AHA.
Email: gsalama@pitt.edu